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A Study of Trastuzumab Emtansine Versus Capecitabine + Lapatinib in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (EMILIA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00829166
First received: January 22, 2009
Last updated: September 10, 2016
Last verified: September 2016
Results First Received: February 22, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Breast Cancer
Interventions: Drug: Trastuzumab emtansine
Drug: Lapatinib
Drug: Capecitabine

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants of "Lapatinib + Capecitabine" arm were allowed to cross over to receive trastuzumab emtansine based on statistically significant Overall Survival (OS) benefit in favor of trastuzumab emtansine demonstrated in second interim analysis (cut-off date 31 July 2012). The safety analysis of the arm was then reported.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenous (IV) infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until disease progression (PD) (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 milligrams per square meter (mg/m^2) orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Participant Flow:   Overall Study
    Trastuzumab Emtansine   Lapatinib + Capecitabine
STARTED   495   496 
Treated   490   488 
COMPLETED   0   0 
NOT COMPLETED   495   496 
Death                305                333 
Lost to Follow-up                5                4 
Physician's Decision                4                3 
Subject's Decision                41                55 
Sponsor’s Decision                137                98 
Reason Not Specified                3                3 



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat (ITT) population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.
Total Total of all reporting groups

Baseline Measures
   Trastuzumab Emtansine   Lapatinib + Capecitabine   Total 
Overall Participants Analyzed 
[Units: Participants]
 495   496   991 
Age 
[Units: Years]
Mean (Standard Deviation)
 52.2  (11.0)   53.2  (10.8)   52.7  (10.9) 
Gender 
[Units: Participants]
     
Female   494   492   986 
Male   1   4   5 


  Outcome Measures
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1.  Primary:   Percentage of Participants With PD or Death as Assessed by an Independent Review Committee (IRC)   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

2.  Primary:   Progression-free Survival (PFS) as Assessed by an IRC (Co-primary Endpoint)   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

3.  Primary:   Percentage of Participants Who Died: Second Interim Analysis   [ Time Frame: From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months) ]

4.  Primary:   Overall Survival: Second Interim Analysis (Co-primary Endpoint)   [ Time Frame: From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months) ]

5.  Primary:   Percentage of Participants Who Died: Final Analysis   [ Time Frame: From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months) ]

6.  Primary:   Overall Survival: Final Analysis   [ Time Frame: From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months) ]

7.  Primary:   Percentage of Participants Who Were Alive at Year 1   [ Time Frame: Year 1 ]

8.  Primary:   Percentage of Participants Who Were Alive at Year 2   [ Time Frame: Year 2 ]

9.  Secondary:   Percentage of Participants With PD or Death as Assessed by the Investigator   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

10.  Secondary:   PFS as Assessed by the Investigator   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

11.  Secondary:   Percentage of Participants With Objective Response (OR) as Assessed by an IRC   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

12.  Secondary:   Duration of Objective Response (DOR) as Assessed by an IRC   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

13.  Secondary:   Percentage of Participants With Clinical Benefit as Assessed by an IRC   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

14.  Secondary:   Percentage of Participants With Treatment Failure   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

15.  Secondary:   Time to Treatment Failure   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

16.  Secondary:   Percentage of Participants With Symptom Progression   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

17.  Secondary:   Time to Symptom Progression   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame Only study-related serious adverse events (SAEs) were reported from randomization to first treatment; all SAEs and non-SAEs were reported from start of treatment until 30 days after treatment; and thereafter only treatment related SAEs were reported until data cut-off date of 21-Sep-2015 (up to 6 years and 7 months). For participants who crossed over from lapatinib + capecitabine to trastuzumab emtansine, data is reported from time of cross-over until 21-Sep-2015 (up to 3 years and 2 months).
Additional Description Safety population included participants who received at least 1 dose of study medication. Safety analyses were based on the actual treatment received.

Frequency Threshold
Threshold above which other adverse events are reported   5  

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.
Lapatinib + Capecitabine/ Trastuzumab Emtansine Participants of "Lapatinib + Capecitabine" arm were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Other Adverse Events
    Trastuzumab Emtansine   Lapatinib + Capecitabine   Lapatinib + Capecitabine/ Trastuzumab Emtansine
Total, other (not including serious) adverse events       
# participants affected / at risk   474/490 (96.73%)   471/488 (96.52%)   115/136 (84.56%) 
Blood and lymphatic system disorders       
Anaemia * 1       
# participants affected / at risk   67/490 (13.67%)   40/488 (8.20%)   11/136 (8.09%) 
Neutropenia * 1       
# participants affected / at risk   37/490 (7.55%)   43/488 (8.81%)   0/136 (0.00%) 
Thrombocytopenia * 1       
# participants affected / at risk   150/490 (30.61%)   13/488 (2.66%)   23/136 (16.91%) 
Eye disorders       
Dry eye * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   7/136 (5.15%) 
Gastrointestinal disorders       
Abdominal pain * 1       
# participants affected / at risk   43/490 (8.78%)   50/488 (10.25%)   0/136 (0.00%) 
Abdominal pain upper * 1       
# participants affected / at risk   60/490 (12.24%)   45/488 (9.22%)   0/136 (0.00%) 
Constipation * 1       
# participants affected / at risk   139/490 (28.37%)   59/488 (12.09%)   22/136 (16.18%) 
Diarrhoea * 1       
# participants affected / at risk   123/490 (25.10%)   385/488 (78.89%)   20/136 (14.71%) 
Dry mouth * 1       
# participants affected / at risk   85/490 (17.35%)   26/488 (5.33%)   20/136 (14.71%) 
Dyspepsia * 1       
# participants affected / at risk   51/490 (10.41%)   57/488 (11.68%)   7/136 (5.15%) 
Gingival bleeding * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   8/136 (5.88%) 
Nausea * 1       
# participants affected / at risk   202/490 (41.22%)   224/488 (45.90%)   35/136 (25.74%) 
Stomatitis * 1       
# participants affected / at risk   20/490 (4.08%)   70/488 (14.34%)   0/136 (0.00%) 
Vomiting * 1       
# participants affected / at risk   98/490 (20.00%)   145/488 (29.71%)   13/136 (9.56%) 
General disorders       
Influenza like illness * 1       
# participants affected / at risk   26/490 (5.31%)   9/488 (1.84%)   13/136 (9.56%) 
Asthenia * 1       
# participants affected / at risk   91/490 (18.57%)   86/488 (17.62%)   23/136 (16.91%) 
Chest pain * 1       
# participants affected / at risk   40/490 (8.16%)   27/488 (5.53%)   0/136 (0.00%) 
Chills * 1       
# participants affected / at risk   42/490 (8.57%)   16/488 (3.28%)   13/136 (9.56%) 
Fatigue * 1       
# participants affected / at risk   180/490 (36.73%)   145/488 (29.71%)   30/136 (22.06%) 
Mucosal inflammation * 1       
# participants affected / at risk   33/490 (6.73%)   93/488 (19.06%)   0/136 (0.00%) 
Oedema peripheral * 1       
# participants affected / at risk   38/490 (7.76%)   38/488 (7.79%)   10/136 (7.35%) 
Pain * 1       
# participants affected / at risk   35/490 (7.14%)   14/488 (2.87%)   0/136 (0.00%) 
Pyrexia * 1       
# participants affected / at risk   95/490 (19.39%)   43/488 (8.81%)   18/136 (13.24%) 
Hepatobiliary disorders       
Hyperbilirubinaemia * 1       
# participants affected / at risk   13/490 (2.65%)   46/488 (9.43%)   0/136 (0.00%) 
Infections and infestations       
Nasopharyngitis * 1       
# participants affected / at risk   50/490 (10.20%)   41/488 (8.40%)   14/136 (10.29%) 
Paronychia * 1       
# participants affected / at risk   2/490 (0.41%)   59/488 (12.09%)   0/136 (0.00%) 
Upper respiratory tract infection * 1       
# participants affected / at risk   56/490 (11.43%)   40/488 (8.20%)   14/136 (10.29%) 
Urinary tract infection * 1       
# participants affected / at risk   52/490 (10.61%)   21/488 (4.30%)   0/136 (0.00%) 
Injury, poisoning and procedural complications       
Infusion related reaction * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   8/136 (5.88%) 
Investigations       
Alanine aminotransferase increased * 1       
# participants affected / at risk   92/490 (18.78%)   48/488 (9.84%)   14/136 (10.29%) 
Aspartate aminotransferase increased * 1       
# participants affected / at risk   123/490 (25.10%)   53/488 (10.86%)   25/136 (18.38%) 
Blood alkaline phosphatase increased * 1       
# participants affected / at risk   26/490 (5.31%)   23/488 (4.71%)   9/136 (6.62%) 
Blood bilirubin increased * 1       
# participants affected / at risk   21/490 (4.29%)   32/488 (6.56%)   11/136 (8.09%) 
Platelet count decreased * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   8/136 (5.88%) 
Weight decreased * 1       
# participants affected / at risk   38/490 (7.76%)   37/488 (7.58%)   7/136 (5.15%) 
Metabolism and nutrition disorders       
Decreased appetite * 1       
# participants affected / at risk   105/490 (21.43%)   117/488 (23.98%)   21/136 (15.44%) 
Dehydration * 1       
# participants affected / at risk   9/490 (1.84%)   25/488 (5.12%)   0/136 (0.00%) 
Hypokalaemia * 1       
# participants affected / at risk   47/490 (9.59%)   45/488 (9.22%)   7/136 (5.15%) 
Musculoskeletal and connective tissue disorders       
Arthralgia * 1       
# participants affected / at risk   102/490 (20.82%)   46/488 (9.43%)   21/136 (15.44%) 
Back pain * 1       
# participants affected / at risk   78/490 (15.92%)   63/488 (12.91%)   9/136 (6.62%) 
Bone pain * 1       
# participants affected / at risk   34/490 (6.94%)   20/488 (4.10%)   0/136 (0.00%) 
Muscle spasms * 1       
# participants affected / at risk   39/490 (7.96%)   22/488 (4.51%)   8/136 (5.88%) 
Musculoskeletal pain * 1       
# participants affected / at risk   46/490 (9.39%)   22/488 (4.51%)   10/136 (7.35%) 
Myalgia * 1       
# participants affected / at risk   70/490 (14.29%)   20/488 (4.10%)   16/136 (11.76%) 
Pain in extremity * 1       
# participants affected / at risk   71/490 (14.49%)   61/488 (12.50%)   8/136 (5.88%) 
Nervous system disorders       
Dizziness * 1       
# participants affected / at risk   62/490 (12.65%)   50/488 (10.25%)   0/136 (0.00%) 
Dysgeusia * 1       
# participants affected / at risk   41/490 (8.37%)   21/488 (4.30%)   0/136 (0.00%) 
Headache * 1       
# participants affected / at risk   146/490 (29.80%)   77/488 (15.78%)   28/136 (20.59%) 
Neuropathy peripheral * 1       
# participants affected / at risk   59/490 (12.04%)   30/488 (6.15%)   16/136 (11.76%) 
Paraesthesia * 1       
# participants affected / at risk   31/490 (6.33%)   20/488 (4.10%)   7/136 (5.15%) 
Peripheral sensory neuropathy * 1       
# participants affected / at risk   36/490 (7.35%)   27/488 (5.53%)   0/136 (0.00%) 
Psychiatric disorders       
Anxiety * 1       
# participants affected / at risk   31/490 (6.33%)   15/488 (3.07%)   0/136 (0.00%) 
Depression * 1       
# participants affected / at risk   27/490 (5.51%)   30/488 (6.15%)   0/136 (0.00%) 
Insomnia * 1       
# participants affected / at risk   69/490 (14.08%)   45/488 (9.22%)   14/136 (10.29%) 
Respiratory, thoracic and mediastinal disorders       
Cough * 1       
# participants affected / at risk   100/490 (20.41%)   68/488 (13.93%)   18/136 (13.24%) 
Dyspnoea * 1       
# participants affected / at risk   61/490 (12.45%)   41/488 (8.40%)   17/136 (12.50%) 
Epistaxis * 1       
# participants affected / at risk   121/490 (24.69%)   44/488 (9.02%)   35/136 (25.74%) 
Oropharyngeal pain * 1       
# participants affected / at risk   24/490 (4.90%)   26/488 (5.33%)   0/136 (0.00%) 
Rhinorrhoea * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   11/136 (8.09%) 
Skin and subcutaneous tissue disorders       
Alopecia * 1       
# participants affected / at risk   19/490 (3.88%)   25/488 (5.12%)   0/136 (0.00%) 
Dermatitis acneiform * 1       
# participants affected / at risk   3/490 (0.61%)   28/488 (5.74%)   0/136 (0.00%) 
Dry skin * 1       
# participants affected / at risk   17/490 (3.47%)   54/488 (11.07%)   8/136 (5.88%) 
Erythema * 1       
# participants affected / at risk   16/490 (3.27%)   25/488 (5.12%)   0/136 (0.00%) 
Nail disorder * 1       
# participants affected / at risk   18/490 (3.67%)   48/488 (9.84%)   0/136 (0.00%) 
Palmar−Plantar erythrodysaesthesia syndrome * 1       
# participants affected / at risk   7/490 (1.43%)   291/488 (59.63%)   7/136 (5.15%) 
Pruritus * 1       
# participants affected / at risk   32/490 (6.53%)   46/488 (9.43%)   7/136 (5.15%) 
Rash * 1       
# participants affected / at risk   64/490 (13.06%)   133/488 (27.25%)   17/136 (12.50%) 
Skin fissures * 1       
# participants affected / at risk   2/490 (0.41%)   27/488 (5.53%)   0/136 (0.00%) 
Skin hyperpigmentation * 1       
# participants affected / at risk   2/490 (0.41%)   25/488 (5.12%)   0/136 (0.00%) 
Vascular disorders       
Hypertension * 1       
# participants affected / at risk   29/490 (5.92%)   11/488 (2.25%)   7/136 (5.15%) 
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA 18.1



  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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